Table 3.

Hereditary Disorders with Hypotonia in the Differential Diagnosis of GARS1 Infantile-Onset Spinal Muscular Atrophy (GARS1-iSMA)

Gene(s) or RegionDiffDx DisorderMOIAdditional Features Overlapping w/GARS1-iSMAFeatures of DiffDx Disorder Not Associated w/GARS1-iSMA
15q11.2-q13 1 Prader-Willi syndrome See footnote 1.Feeding difficultiesRarely assoc w/poor respiratory effort
CHAT
CHRNE
COLQ
DOK7
GFPT1
RAPSN 2		 Congenital myasthenic syndromes AR
AD		HypotoniaOphthalmoplegia, ptosis, episodic respiratory failure
COL6A1/2/3FKRP
FKTN
CRPPA (ISPD)
LAMA2
LARGE1
LMNA
POMGNT1
POMT1
POMT2
SELENON
(many additional genes) 3		Congenital muscular dystrophyAR
AD		Muscle weakness, respiratory failure, epilepsy↑ CK, CNS malformation & leukoencephalopathy, eye involvement
DMPK Congenital myotonic dystrophy type 1ADMuscle weaknessMarked facial weakness w/"myopathic" facies
GAA Infantile-onset Pompe diseaseARFeeding difficulties, respiratory failure, hypotoniaEKG abnormalities, cardiomegaly
IGHMBP2 AR dSMA 1 4 (SMARD) (OMIM 604320)ARAreflexia, respiratory failureDiaphragmatic paralysis
PEX family of genes Zellweger spectrum disorder AR 5Muscle weakness, poor respiratory effortHepatomegaly, large anterior fontanelle, CNS involvement
SMN1 Spinal muscular atrophy ARAreflexia, respiratory failure, tongue fasciculationsSensory involvement, predominant distal weakness
UBA1 X-linked infantile SMA XLWeakness, areflexia, tongue fasciculationsMultiple congenital contractures, intrauterine fractures

AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; DiffDx = differential diagnosis; dSMA = distal spinal muscular atrophy; iSMA = infantile spinal muscular atrophy; MOI = mode of inheritance; SMARD = spinal muscular atrophy with respiratory distress; XL = X-linked

1.

Prader-Willi syndrome (PWS) is caused by an absence of expression of imprinted genes in the paternally derived PWS / Angelman syndrome region (15q11.2-q13) of chromosome 15 by one of several genetic mechanisms (paternal deletion, maternal uniparental disomy 15, and rarely an imprinting defect). The risk to the sibs of an affected child of having PWS depends on the genetic mechanism that resulted in the absence of expression of the paternally contributed 15q11.2-q13 region.

2.

Pathogenic variants in one of multiple genes encoding proteins expressed at the neuromuscular junction are currently known to be associated with subtypes of CMS. The most commonly associated genes include those listed in the table (see Congenital Myasthenic Syndromes).

3.

Multiple genes are associated with congenital muscular dystrophy (CMD). The frequency of CMD subtypes vary by population [Bönnemann et al 2014]. Selected examples of some of the more commonly associated genes are listed in the table.

4.

SMARD spans a phenotypic spectrum [Guenther et al 2007].

5.

Zellweger spectrum disorder (ZSD) is typically inherited in an autosomal recessive manner (one PEX6 variant, p.Arg860Trp, has been associated with ZSD in the heterozygous state).

From: GARS1-Associated Axonal Neuropathy

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